HUT64041A - Process for producing imidazole derivatives comprising (biphenylsulfonyl)-urea or (biphenylsulfonyl)-urethane derivative side chain, as well as pharmaceutical compositions comprising such compounds - Google Patents

Abstract

Compounds of the formula (I) <IMAGE> in which R<1> is, for example, ethyl, R<2> is, for example, methyl, n is, for example, zero, R<3> is, for example, COOH and R<4> is, for example, SO2NHCONHCH3 are highly active antagonists of angiotensin II receptors.

Description

The present invention relates to novel imidazole derivatives containing a (biphenylsulfonyl) urea or (biphenylsulfonyl) urethane side chain. These compounds are antagonists of the angiotensin II receptor. The invention also relates to pharmaceutical compositions containing such compounds as active ingredients and to the preparation of novel compounds and compositions.

There is growing interest in the development of new angiotensin-II receptor antagonists in the field of novel drug production. For example, in European Patent Application 0 028 834, 1-benzyl substituted imidazole derivatives, European Patent Application 0 253 310, imidazole derivatives having a diaryl carboxylic acid group, European Patent Application 0 324 377, and diaryl tetrazolyl having a diaryl carboxylic acid residue, and they disclose their use as angiotensin II receptor antagonists.

European Patent Application 0 503 162 also describes 2- (n-butyl) substituted imidazole derivatives having the structure (biphenylsulfonyl) urea or (biphenylsulfonyl) urethane. The latter compounds also have angiotensin-II receptor antagonist activity.

The invention describes a new, (biphenyl-sulfonyl) urea or carrier (biphenyl-sulfonyl) urea or a (biphenyl-sulfonyl) -carbamate side chain imidazole derivatives, which bear a specific substituent R ¹ of the imidazole 2-position, and both in vitro , all under surprisingly potent angiotensin-II receptor antagonist activity in vivo. More particularly, the present invention relates to (I): ··························

Refers to compounds of Formula 3 and their physiologically acceptable salts, wherein:

R ¹ is C 1 -C 3 alkyl, preferably n-propyl or ethyl, but especially n-propyl;

R ² is C 1-6 alkyl, especially methyl; C3-C7 cycloalkyl; phenyl or benzyl;

R ³ is hydrogen; -CH ₂ OR ⁵ , -CO-R ⁶ or -O R ⁷ ;

^R4 -SO2NR ⁷ R ^8, -SO2NR ⁸ -CO-NR ⁷ R ^9, -SO 2 ^-NH-COO-R7, -S02-NH-S0 ₂ NR ⁷ R ^9, -SO 2 -NH-CO-R ⁷ , -SO 2 -NH-SO ₂ -R ⁷ or -SO ₂ N = CH-N (CH 3) ₂ ;

R ⁵ is hydrogen or C 1-6 alkyl;

R ⁶ is hydrogen or -O R ⁷ ;

R ⁷ and R ⁹ are the same or different and are hydrogen; C 1-6 alkyl, preferably methyl, ethyl or propyl; C3-C8 cycloalkyl; (C3-C6) cycloalkyl (C1-C3) alkyl; (C6-C12) aryl, preferably phenyl, (C6-C10) aryl (C1-C4) alkyl, preferably benzyl, optionally partially or fully hydrogenated (C 1 -C 9) heteroaryl, optionally partially or fully hydrogenated (C 1 -C 9) heteroaryl (C 1 -C 3 alkyl) in the heteroaryl moiety, halogen, hydroxy, (C 1 -C 4) alkyl, methoxy; , with nitro or cyano ····

- 4 mono-or di-substituted, identical or different,

C 6 -C 12 aryl (preferably phenyl), (C 6 -C 10 aryl) - (C 1 -C 4) alkyl (preferably benzyl), optionally partially or fully hydrogenated C 1 -C 9 heteroaryl, optionally partially in the heteroaryl moiety or fully hydrogenated (C 1 -C 9) heteroaryl (C 1 -C 3) alkyl; or C 2 -C 6 alkenyl or C 3 -C 6 alkenoyl; C3-C8 cycloalkenyl; (C3-C8) cycloalkenyl (C1-C3) alkyl; (C 6 -C 10 aryl) (C 3 -C 6) alkenyl; (C 1 -C 9 heteroaryl) (C 3 -C 6 alkenyl); or C 3-6 alkynyl;

R ^{8 is} hydrogen; and n is 0, 1 or 2.

Preferred are compounds and their physiologically acceptable salts wherein R ^{1 in the} formula (I) is ethyl or n-propyl, in particular n-propyl.

Further preferred are compounds and physiologically acceptable salts thereof wherein R ² is C 1 -C 6 aryl, R ³ is -COR ⁶ ; n is 0;

R ⁴ is -SO 2 -NH-CO-OR ⁷ , -SO 2 -NH-CO-NHR ⁷ or

-SO ₂ -NH-CO-R ⁷ ;

• ·

• ·· • ·· ·

^R6 is hydrogen, or the same as R ^7, respectively; and

R ^{7 is} hydrogen or C 1-6 alkyl.

Alkyl, alkenyl and alkynyl groups may be straight or branched.

By cycloalkyl is also meant alkyl substituted cycloalkyl.

C 6 -C 12 aryl can be, for example, phenyl, naphthyl or biphenyl, preferably phenyl.

C 1-9 heteroaryl, in particular, refers to groups derived from the phenyl or naphthyl group by replacing one or more = CH with nitrogen and / or having at least two adjacent = CH (by the formation of a five-membered aromatic ring) sulfur or substituted with oxygen or -NH-. Further, one or both atoms of the condensation site of bicyclic groups (e.g., indolizinyl) may be nitrogen.

In particular, the heteroaryl group is furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, , indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl sweep.

The chiral centers that may be present may have both the (R) and the (S) configuration.

• 4 • · · 4 • · · 4 ·

4 4 44 ···· ··· · · · · · · · · · · · · · ·

Physiologically acceptable salts of the compounds of formula (I) include organic or inorganic salts as defined in Remington's Pharmaceutical Sciences [17]. 1418, (1985)].

Sodium, potassium, calcium or ammonium salts are preferred for acid groups based on physical and chemical stability and solubility; while basic groups include hydrochloric acid, sulfuric acid, phosphoric acid and salts of carboxylic and sulfonic acids such as acetic, citric, benzoic, maleic, fumaric, tartaric and p-toluenesulfonic acids as acid components.

The present invention also relates to the preparation of novel compounds of formula I and their physiologically acceptable salts. The preparation according to the invention is carried out by reacting a compound of formula II wherein R ¹ , R ² , R ³ and n are as defined above with a compound of formula III wherein R ⁴ is as defined above and U is a leaving group. alkylation, followed by cleavage of the protecting groups which may be introduced temporarily, optionally converting the resulting sulfonamide of formula (I) into a urethane of formula (I), optionally converting the resulting sulfonamide of formula (I) into a sulfonyl of formula (I) to a urea and optionally converting the compound of formula (I) thus obtained into a physiologically acceptable salt.

Suitable U leaving groups are nucleofugic groups [see Angew. Chem., 72, 71 (1960)] such as halogen, ρ-toluenesulfonate, mesylate or triflate tube · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ···

- 7 ports.

The preparation of starting materials of formula (II) is known, inter alia, from U.S. Patent No. 4,355,044 and European Patent Application Nos. 0 324 377 and 0 323 841, cited above.

Further procedures are disclosed in G. L'abbe, Chem. Port. 69, 345 (1969)], T. Srodsky (The Chemistry of the Azido Group, Wiley, New York, p. 331, 1971), and H. Wamhoff (Comprehensive Heterocyclic Chemistry) (Comparative Heterocyclic Chemistry) chemistry) and S. Katritzky (Pergamon Press, New York (1984)).

Compounds of formula (II) may also be prepared by starting from 1-cyanoglyoxylic acid 2-oxime derivatives, reducing the oxime with reducing agents known in the art, and adding suitable mercaptans to the nitrile group, using appropriate protecting groups, to yield water precursors. can be cyclized to imidazole derivatives. The cyclization step includes, but is not limited to, a mixture of phosphorus pentachloride and dimethylaminopyridine (DMAP in short) and phosphorus oxychloride and thionyl chloride or mixtures thereof with DMAP.

For example, the corresponding benzyl halides, tosylates, mesylates or triflates and the corresponding alkyl halides, tosylates, mesylates or triflates can be used to alkylate the compounds of formula II.

These compounds are prepared by known methods, for example, the corresponding methyl-containing precursors are halogenated. ·

- 8 views. N-bromosuccinimide is preferably used for this purpose [see, e.g., J. Org. Chem., 44, 4733 (1979); and Helv. Chim. Acta 62, 2661 (1979)].

Biphenyl derivatives can be prepared, for example, by coupling arylboronic acid derivatives and the corresponding aryl halides in the presence of transition metal catalysts, in particular palladium. A description of this reaction can be found, for example, in R.B. Miller et al. (Organometallics 3: 1261 (1984)) or A. Zuzuki et al., Synthetic Commun. 11, 513 (1981)].

The sulfonylurethane derivatives of formula I can be prepared from the corresponding sulfonamides of formula I by reaction with chloroformic acid esters in an inert solvent in the presence of a base such as potassium carbonate, preferably at the boiling point of the appropriate solvent.

Alternatively, the sulfonylureas of formula (I) may be prepared by reaction of the corresponding sulfonamides of the general formula (I) with isocyanates or by reaction of the sulfonamides with the corresponding 2,2,2-trichloroacetyl derivative of the corresponding amine. in a solvent (e.g., dimethyl sulfoxide (DMSO for short)); and reacting the sulfonylurethanes of formula (I) with the corresponding amine in an inert, high-boiling solvent, such as toluene, at a temperature up to the boiling point of that solvent.

Sulfonylsulfonamides are obtained analogously from the corresponding sulfonamides by reaction with sulfonic acid chlorides ······················································································ ··

Or sulfamoyl chlorides.

The sulfonamide moiety may be formed from an amino group, if necessary, by Meerwein rearrangement. To this end, the hydrochloride of the amine is first diazotized and then treated with sulfur dioxide in glacial acetic acid in the presence of a copper catalyst. The product thus obtained is reacted with ammonia to give the sulfonamido group.

The sulfonamido group may be temporarily protected, for example, in the form of the 2-N, N- (dimethylaminoformyl) sulfonamido group. Alternatively, this is accomplished by reacting either the corresponding sulfonamide compound with N, N-dimethylformamide dimethylacetal or the corresponding sulfonamide compound with Ν, Ν-dimethylformamide (DMF for short), such as thionyl chloride, in the presence of phosphorus oxychloride, phosphorus pentachloride or ethyl chloroformate. The protecting group thus temporarily introduced may be removed under either basic or acidic conditions.

Alternatively, a suitable thiophenol may be oxidized with chlorine and the product thus obtained reacted with ammonia to give the corresponding sulfonamide.

Alkylation is carried out in analogy to the procedures known in principle below.

It is possible to first convert an imidazole derivative of formula II into a metal derivative in the presence of a base. Suitable bases for this purpose are lithium, sodium or potassium hydride in DMF or DMSO; or metal alkanolates of the formula MOR, wherein R is methyl, ethyl or tert-butyl. The latter reaction is appropriate · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ···

- 10 alcohols, DMF or DMSO. The metal salt of the imidazole derivative thus obtained is dissolved in an aprotic solvent such as DMF or DMSO and reacted with an appropriate amount of alkylating agent.

Deprotonation of imidazole derivatives can also be achieved by reacting them with potassium carbonate in DMF or DMSO.

The oxidation of thio compounds of the formula I, wherein n is zero, to the corresponding sulfones, where n is 2, or sulfoxides, where n is 1, can be carried out with peracids in a suitable solvent, such as dichloromethane.

The reaction is carried out at a temperature below room temperature to the reflux temperature of the reaction mixture, preferably at a temperature between 20 ° C and the reflux temperature of the reaction mixture, for a period of about 1 to 10 hours.

The compounds of formula (I) of the present invention have antagonistic effects on angiotensin II receptors and are useful, for example, in the treatment of hypertension induced by angiotensin II. However, their potential uses include treating heart failure, protecting myocardial infarction, myocardial infarction, cardiac hypertrophy, arteriosclerosis, kidney disease, renal failure, and cardiovascular diseases of the brain such as transient ischemic attack and stroke.

Renin is a proteolytic enzyme belonging to the group of asparagil proteases which, by various stimuli such as volume depletion, sodium deficiency, stimulation of beta receptors, responds from the juxtaglomerular cells of the kidney to the bloodstream. 4 4 4 4 4 · *

4444 ·· · · 44 ··· 4

11, where it cleaves the angiotensin-I decapeptide from the liver-selected angiotensin gene. The latter is converted to angiotensin ΙΙ by the enzyme angiotensin convertase (ACE in short), which plays an important role in controlling blood pressure by directly increasing blood pressure due to the constriction of blood vessels. In addition, it stimulates the secretion of aldosterone from the adrenal gland, thereby increasing the volume of extracellular fluid by inhibiting sodium excretion, which also contributes to the rise in blood pressure.

Post-receptor effects include stimulation of phosphoinositide conversion (Ca ²⁺ release), activation of protein kinase C, and enhancement of c-AMP-dependent hormone receptors.

The affinity of the compounds of formula (I) for angiotensin II receptors can be determined by measuring the displacement of ¹²⁵ J-angiotensin II or ³ H-angiotensin-II from the membranes of the glomerulosa cells from the bovine adrenal zone. For this purpose, the membrane composition was suspended in a pH 7.4 buffer.

In order to prevent the degradation of the radioligand during incubation, aprotinin, a peptidase inhibitor, is used. Further, about 14,000 cpm of labeled material with a specific activity of 74 TBq / mmol (purchased from Amersham Buchler, Braunschweig, Federal Republic of Germany) is used and the receptor protein is used in an amount that binds 50% of the labeled material. The reaction was initiated by 50 μΐ membrane suspension. «· ♦ ·« «« «« ««

- 12 zions are added to the 100 μΐ buffer containing aprotinin;

μΐ buffer solution, with or without addition of angiotensin II or receptor antagonist; and 50 μΐ of labeled material is used. After incubation for 60 minutes at 25 ° C, the bound and free radio ligand were isolated by filtration (e.g., Whatman ^R GFIC filters using the Skatron ^R cell harvester).

Nonspecific binding is inhibited by treating the filter with 0.3% polyethyleneimine at pH (see, e.g., Sigma, No. 3143). Radioactivity is measured in a gamma scintillation counter to determine the degree of repression of the radioligand from the receptor.

IC 50 values (IC 50 is the concentration of inhibitor that suppresses 50% of the ligand) are described in J. Theor. Biol. 59, 253 (1970). These values are in the range of 1x10 ^-4 and 1x10 ^-9 M for compounds of formula (I).

Similarly, the affinity of the compounds of formula (I) for angiotensin II receptors can be determined by suppressing the ¹²⁵ J-angiotensin II or ³ H-angiotensin II from various other organs (e.g., liver, lung, adrenal gland, brain). receptor preparations.

For this purpose, the membrane preparation was incubated in buffer (containing, for example, 20 mM Tris, pH 7.4, 1 35 mM sodium chloride, 10 mM potassium chloride, 10 mM magnesium chloride, glucose, 0.2% deer13 bovine serum albumin, 0.3 mmol / l PMSF and 0.1 mmol / l bacitracin as protease inhibitors) and then radiolabeled with angiotensin-II and at various concentrations. incubated for 90 minutes at 25 ° C. The bound and free radioligand are then separated by filtration on a microfibre filter (e.g., GF51, Schleiher & Schull, Skatron ^R cell harvester).

The radioactivity bound by the receptors on the filters is measured by a beta or gamma spectrometer to determine the degree of suppression of the radio ligand by the test compounds. The degree of suppression of radioligands is expressed as IC50 values (the concentration of inhibitor that suppresses 50% of the bound radioligand from the receptor). IC5Q values can be calculated using a PC program on a computer (e.g., Ligand, GA McPherson 1985, Elsevier-BIOSOFT, 68 Hills Road, Cambridge CB 211LA, United Kingdom). For the general formulas (I), the measured values are available for the IC5Q lxlO lxlO ^-5 and ^-11 M range.

The antagonistic activity of the compounds of formula (I) can be determined in vivo by their inhibitory effect on angiotensin-II-induced hypertension in Sprague-Dawley rats (Mollegard, Denmark). The active compounds were administered intravenously into the penis of the animals.

After a waiting time of 20 minutes to prepare the animal and then to stabilize the hemodynamic parameters

- 14, 5 and 10 mg of angiotensin-II in 0.1 ml aqueous solution were administered at 3-minute intervals. Compounds of formula I dissolved in distilled water, optionally in distilled water containing 10% ethanol and / or by addition of base (at pH below 10) or addition of acid (at pH above 3) at doses of 1 to 300 mg / kg intravenously, or

It was administered intraduodenally at doses of 5-1000 gg / kg.

Blood pressure response occurs 20, 40 and 60 minutes after angiotensin II injection and 10 minutes after intravenous administration, respectively.

The compounds of formula (I) are particularly effective when administered intravenously at a dose of from 1 to 300 mg / kg, and when administered intraduodenally at a dose of from 5 to 300 mg / kg.

The invention also encompasses pharmaceutical compositions consisting essentially of a compound of formula (I) and optionally other active ingredients, such as urinary capsules or non-steroidal anti-inflammatory drugs. The compounds of formula (I) may also be used as diagnostics for testing the renin-angiotensin system.

The pharmaceutical compositions of the present invention comprise an effective amount of a compound of formula (I) and, optionally, other active ingredients in admixture with an inorganic or organic pharmaceutical carrier and optionally further additives and / or excipients. These pharmaceutical preparations can be applied to the nasal mucosa by intravenous, intravenous, subcutaneous or oral route. The dose of the active ingredient depends on the breed, body weight, age and mode of administration of the warm-blooded animal.

The pharmaceutical compositions of the present invention may be prepared by known dissolution, mixing, granulating or pelleting techniques.

For the purpose of preparing the oral form, the active compound is formulated in a suitable dosage form with admixtures generally employed for this purpose, such as carriers, stabilizers or inert diluents; such dosage forms include tablets, dragees, capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. Inert carriers include, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch. The formulation may be carried out with dry or wet granules and may be carried out. Oily vehicles or solvents include, for example, vegetable or animal oils, such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compound, or a physiologically acceptable salt thereof, is optionally formulated in solution, suspension or emulsion with substances commonly used for this purpose, for example, as solubilizing agents, emulsifiers, or other excipients. Examples of solvents are water, physiological saline, or alcohols such as ethanol, propanediol, or glycerol.

9 9 te9 999

9 9 9 · *

9999 99 9 9999 999 Cerin and mixtures of sugar solutions, such as glucose or mannitol, and mixtures of the solvents mentioned may be included.

The invention is further illustrated by the following non-limiting examples. In these examples, the following abbreviations are used:

Ac: acetyl

DMF: N, N-dimethylformamide

DME: dimethoxyethane

EA: ethyl acetate (in chromatographic developer)

DCI: desorption-chemical ionization

FAB: Speed Bombardment (Mass Spectrum)

m.p .: melting point h: hour (s) min: minute (s)

DKM: dichloromethane

Example 1 1 - {[2 '- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) - Preparation of Imidazole-5-carboxylic acid ethyl ester (Compound 1)

a) Preparation of 2-amino-2-cyanoacetic acid ethyl ester for a mixture of g (0.492 mol) 2-cyanoglyoxylic acid ethyl ester 2-oxime in 700 ml water and 560 ml saturated sodium bicarbonate solution 228 g (1.3 mmol) of sodium dithionite are added over 20 minutes at room temperature and the reaction mixture is stirred at 35 ° C for 12 hours. After cooling, it is saturated with sodium chloride and extracted with dichloromethane. The organic phase is anhydrous sodium sulphate · · ·

- Dry on 17 wood and evaporate the solution to dryness

The title product of step a) is obtained as an oil in 30 g; Rf (using dichloromethane: methanol = 9: 1 as developing agent) 0.6.

b) Preparation of 2-Cyano-2- (n-propylcarbonylamino) -acetic acid ethyl ester

30 g (0.233 mol) of the product prepared in step a) above and 250 ml of abs. To a solution of dichloromethane (briefly: DKM) is added pyridine (18.9 mL, 0.233 mol) and a solution of butyric acid chloride (24.2 mL, 0.23 mol) in DKM (25 mL) is added dropwise at 0-5 ° C. . After stirring for 12 hours at room temperature, the organic phase was washed three times with water, once with brine, dried over anhydrous sodium sulfate and evaporated. The product was recrystallized from diisopropyl ether to give the title compound of Step b, 29.5 g, Rf (DKM / MCON 9: 1) 0.7, mp 106 ° C.

c) Preparation of 3-Amino-2- (n-propylcarbonylamino) -3- (methylthio) acrylic acid ethyl ester

To a mixture of 29.5 g (0.149 mol) of the product obtained in step b), 2.05 ml (0.145 mol) of triethylamine and 500 ml of ethanol is added 14.3 g (0.297 mol) of liquid methylmercaptan at room temperature. After standing at room temperature for 4 days, the solvent was removed and the residue was recrystallized from diisopropyl ether. Yield: 36.2 g (Rf = 0.4 (DKM / Min. 9: 1)), m.p. 119 ° C.

d) Preparation of 2- (η-Propyl) -4- (methylthio) imidazole-5-carboxylic acid ethyl ester

To a mixture of phosphorus pentachloride (29.16 g, 0.142 mol) in DKM (240 mL) was added dropwise at -78 ° C a solution of 4- (dimethylamino) pyridine (19.3 g, 0.157 mol) in DKM (120 mL) and A solution of 6 g (0.071 mol) of the compound obtained in the preceding step c) and 200 ml of DKM is added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2.5 hours. At this time, 1.6 L of 1N sodium bicarbonate solution was added dropwise under ice-cooling, stirring was continued for 1 hour, and the mixture was allowed to stand overnight. After separation, the aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 4: 1 DKM / ethyl acetate. The title product of Step d) is thus obtained as an oil (5.6 g, Rf 0.4 (DKM / EA 4: 1)).

Mass spectrum (DCI): 229 (M + H).

e) Preparation of 2-sulfonamido-bromobenzene

O-Bromoaniline (51.6 g, 0.3 mol) was added to 100 ml of concentrated hydrochloric acid and 30 ml of glacial acetic acid under argon, and a solution of 22.4 g of sodium nitrite in 30 ml of water was added dropwise at -10 ° C. the reaction mixture was stirred at -5 ° C for 60 minutes. The solution thus obtained was added dropwise to a solution of 7 g of CUCl2.2H2O and 0.5 g of CuCl in 300 ml of glacial acetic acid saturated with sulfur dioxide. The reaction mixture was stirred at room temperature for 60 minutes, then mixed with ice and water. «· ·· · ········

Pour 19, extract with ether. The ether extract was washed with saturated sodium bicarbonate solution, then with water, dried over magnesium sulfate and evaporated. The resulting sulfonyl chloride (67.8 g) was dissolved in acetone (500 mL) and treated with concentrated ammonia (300 mL) under cooling. After removal of the acetone, the resulting slurry was diluted with water, the white crystalline precipitate was filtered off with suction, washed with water and dried in a very good vacuum. This gives the title product of step e) which is used in the next step without purification. M.p. 190 ° C.

f) Preparation of 2- (Ν, Ν-Dimethylaminoformylsulfonamido) bromobenzene

0.236 mol of the compound prepared in the preceding step e);

150 ml abs. DMF solution was treated with 40 ml of N, N-dimethylformamide acetal and the reaction mixture was stirred at room temperature for 2 hours. The solution was poured into 200 ml of a 1: 1 mixture of 5% sodium bisulfate solution and ice, and the precipitate was filtered off with suction, washed with water and dried in vacuo to give the title compound of step f in 67 g, m.p. 148 ° C, Rf 0.1 (silica gel, 1: 1 EA / heptane).

Mass spectrum (DCI): 291/293 (M + H).

g) Preparation of 4'-Methyl-biphenyl-2- (Ν, Ν-dimethylaminoformyl) sulfonamide Compound prepared in the preceding step g (37.9 mmol), 1 g triphenylphosphine, 8 g sodium carbonate , To a mixture of 150 ml of toluene and 40 ml of water, under argon, first 420 mg of palladium (II) acetate, followed by 5.66 g (41.9 ···· · · · · · · · · · · · · · · · · · · · · · · · · ·

Toluylboronic acid (1.times.7 mmol) was added, the reaction mixture was refluxed for 4 hours, evaporated and the residue was taken up in a mixture of ethyl acetate (500 mL) and water (500 mL). The precipitate formed is filtered off: This is the title compound of step g). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate. An additional amount of the title product is obtained. The total yield of the product of step g is 7.6 g, m.p. 181-184 ° C, Rf = 0.2 (silica gel, 1: 1 EA / heptane).

Mass spectrum (DCI): 303 (M + H).

h) Preparation of 4 '- (Bromomethyl) biphenyl-2- (N, N-dimethylaminoformyl) sulfonamide

A mixture of 7.4 g (0.025 mol) of the compound from step g), 4.6 g (0.026 mol) of N-bromosuccinimide, 130 ml of chlorobenzene and 300 mg of benzoyl peroxide is heated under reflux for 2 hours. After cooling, 50 ml of a saturated sodium sulfite solution are added, the organic phase is separated off and washed successively with saturated sodium bicarbonate solution, water, and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was stirred with ethyl acetate and the precipitate was filtered off with suction. Yield: 6.7 g, m.p. 168-170 ° C, Rf = 0.5 (silica gel, EA).

Mass spectrum (DCI): 381/383 (M + H).

i) 1 - {[2 '- (N, N-Dimethylaminoformylsulfonamido) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole Preparation of Ethyl-5-Carboxylic Acid • · · ·································································································································· ······ "· · ·

K - 21 2.0 9 (8.75 mmol) of the compound obtained in the previous step d), 4.15 g (8.75 mmol) of the compound obtained in the previous h) (75% purity) and 1.25 g (9%). (0 mmol) of potassium carbonate in 50 mL of abs. Stir in DMF overnight at room temperature and evaporate. The residue was dissolved in 400 ml of ethyl acetate, the ethyl acetate solution was washed three times with water, dried over anhydrous sodium sulfate and evaporated. The residue is mixed with ethanol and diisopropyl ether and the precipitate is filtered off with suction. Yield: 4.14 g, m.p. 169-171 ° C, Rf 0.4 (silica gel, EA).

Mass Spectrum (FAB): 529 (M + H).

j) Preparation of 1 - {[2- (Sulfonamido) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5-carboxylic acid ethyl ester g A mixture of the compound prepared in (i) (7.60 mmol), methanol (20 ml) and concentrated hydrochloric acid (20 ml) was refluxed for 3 hours, then allowed to cool to room temperature and the solvent was distilled off. The remaining aqueous solution was adjusted to pH 5-6 with 6N sodium hydroxide solution and extracted several times with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated. The foamy residue was mixed with ethanol and diisopropyl ether and the resulting precipitate was filtered off with suction. Yield: 3 g, m.p. 125-127 ° C, Rf 0.7 (silica gel, EA).

Mass Spectrum (FAB): 474 (M + H).

··················································································································································· · 22k) 1 - {[2- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) Preparation of ethylimidazole-5-carboxylic acid ethyl ester for the compound prepared in step j above (4.22 moles) in ml abs. anhydrous potassium carbonate (1.75 g, 12.66 mmol) in acetone was added and the reaction mixture was refluxed for 30 minutes. At this time, propyl isocyanate (395 μΐ, 4.22 mmol) was added and the reaction mixture was stirred at reflux for 1 hour. After cooling, 15 ml of 2N hydrochloric acid are added, the mixture is concentrated in vacuo and the residue is extracted several times with DKM. The organic layer was dried over anhydrous sodium sulfate, evaporated and the residue was recrystallized from ethyl acetate. Yield: 1.9 g, m.p. 160-165 ° C, Rf 0.25 (silica gel, EA / heptane 2: 1).

Mass Spectrum (FAB): 559 (M + H).

Example 2 1 - {[2 '- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) - imidazole-5-carboxylic acid (Compound 2)

A mixture of 700 mg (1.25 mmol) of the compound of Example 1 (k) (final product of Example 1), 40 ml of methanol and 10 ml of 2N sodium hydroxide solution was stirred at room temperature for 3 days and the solvent removed in vacuo. The remaining aqueous solution was adjusted to pH 6 with 2N hydrochloric acid, and the precipitate was filtered off with suction and dried under high vacuum. Thus, the title compound of Example 2 is 600 mg ho · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «« ··· ···

M.p. 133-135 ° C, Rf 0.19 (silica gel, DKM / methanol 10: 1).

Mass Spectrum (FAB): 531 (M + H).

Example 3 1 - {[2 '- (Ethoxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5- Preparation of ethyl carboxylic acid (compound of formula 3)

1.5 g (3.17 mmol) of the compound prepared in Example 1 (j) under argon gas are dissolved in 25 ml of abs. After stirring with DME, 0.876 (6.34 mmol) potassium carbonate and 0.35 mL (3.17 mmol) ethyl chloroformate, reflux for 3 hours and remove as much of the solvent as possible. the resulting solution was adjusted to pH 4 with 10% potassium dihydrogen phosphate solution and extracted several times with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue dried under high vacuum. This gave 1.79 g of the title compound as a yellow foam, Rf = 0.5 (silica gel, EA).

Mass Spectrum (FAB): 546 (M + H).

Example 4 1 - {[2- (Ethoxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5-carboxylic acid Preparation of compound (4)

A mixture of the compound of Example 3 (500 mg, 0.92 mmol) in ethanol (2.5 ml) and 2N sodium hydroxide solution (2.5 ml) was stirred at room temperature for 24 hours and the solvent was removed under reduced pressure. · · · · ·····································································•

- 24 removed. The remaining aqueous solution was treated with 2N hydrochloric acid

The pH is adjusted to 5 and the precipitate is filtered off with suction. The title compound was obtained in a yield of 380 mg as a pale yellow solid, m.p. 156-160 ° C, Rf 0.3 (silica gel, DKM / methanol 9: 1).

Mass Spectrum (FAB): 518 (M + H).

Example 5 1 - {[2 '- (Methylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-ethyl-4- (methylthio) imidazole-5-carboxylic acid Preparation of ethyl ester (5)

a) Preparation of 2-Cyano-2- (ethylcarbonylamino) -acetic acid ethyl ester

This compound was prepared according to the procedure of Example 1 (b), but instead of butyric acid chloride was reacted with the product of Example 1 (a) with propionic acid chloride. Yield: 12.8 g (0.1 mol) of the product of Example 1, Step a), 11.4 g of the title compound of Example 5, Step a, mp 111-113 ° C, Rf 0.6. (on silica gel, EA)

Mass spectrum (DCI): 185 (M + H).

b) Preparation of 3-Amino-2- (ethylcarbonylamino) -3- (methylthio) acrylic acid ethyl ester

This compound was prepared in a similar manner to that described in Example 1 (c), mp 127 ° C, Rf 0.18 (silica gel, EA).

Mass spectrum (DCI): 233 (M + H).

··· ··························································································•

c) Preparation of 2-Ethyl-4- (methylthio) imidazole-5-carboxylic acid ethyl ester

This compound was prepared in a similar manner to that described in Example 1 (d), m.p. 141-143 ° C, Rf 0.4 (silica gel, EA).

Mass spectrum (DCI): 215 (M + H).

d) 1 - {[- 2 '- (Ν, Ν-Dimethylamino-formylsulfonamido) -biphenyl-4-yl] -methyl} -2-ethyl-4- (methylthio) -imidazole-5- Preparation of ethyl carboxylic acid

This compound was prepared from the compound of Example 5 (c) and the compound of Example 1 (h) according to the procedure of Example 1 (i), m.p. 189-194 ° C, Rf = 0.3 (on silica gel). EA).

Mass Spectrum (FAB): 515 (M + H).

e) Preparation of 1- [2 '- (Sulfonamido-biphenyl-4-yl) -methyl] -2-ethyl-4- (methylthio) -imidazole-5-carboxylic acid ethyl ester

This compound was prepared from the product of Example 5 (d) according to the procedure of Example 1 (j), m.p. 153-155 ° C, Rf 0.5 (silica gel, EA).

Mass Spectrum (FAB): 460 (M + H).

f) Preparation of 2,2,2-Trichloro-N-methylacetamide

I

1.6 g (51.5 mmol) of methylamine are liquefied and 20 ml of abs. dissolved in dioxane, triethylamine (7.14 mL, 51.5 mmol);

Trichloroacetyl chloride (5.7 mL, 51.5 mmol) in 10 mL abs. a solution of dioxane was added and the resulting solution was stirred at room temperature for 3 hours. Water is then added, the pH of the solution is adjusted to about 1 with 2N hydrochloric acid, and the precipitate is filtered off with suction (······· · · · · · · · · · · · · · · · · · · · · · · · · · * ···· · · · · · ··················•

- 26 pieces. Thus, the title compound of Example 5, Step f) was obtained

Yield: 7.6 g, m.p. 90-95 ° C.

g) 1 - {[- 2 '- (Methylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-ethyl-4- (methylthio) imidazole-5-carboxylic acid; Preparation of ethyl ester

The compound prepared in Example 5 (e) (135 mg, 0.316 mmol) and 2 mL of abs. To the DMSO mixture, 38 mg (0.1 mmol) of powdered sodium hydroxide and 61 mg (0.348 mmol) of Example 5 (f) were added under argon and the reaction mixture was stirred for 30 minutes at 80 ° C and poured into ice water. acidified with hydrochloric acid and extracted several times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The crystalline residue was stirred with a small amount of ethyl acetate and the precipitate was filtered off with suction. The title compound of Step g, Example 5, m.p. 220-223 ° C, Rf 0.6 (silica gel, DKM / methanol 9: 1) is obtained in 97 mg.

Mass Spectrum (FAB): 517 (M + H).

Example 6 1 - {[2 '- (Methylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-ethyl-4- (methylthio) imidazole-5-carboxylic acid [ (Compound 6)

The title compound was prepared from the compound prepared in Example 5 (g) according to the procedure described in Example 2. This gave 40.5 g of the title ester from 50 mg (0.1 mmol) of the title compound, m.p. 155 ° C, Rf 0.46 (silica gel, 9: 1: 0.2 DKM / methanol / acetic acid).

· ········· · · ·····························································································································································································································································································•

- 27 Mass Spectrum (FAB): 489 (M + H).

Example 7 1 - {[2 '- (Ethoxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-ethyl-4- (methylthio) imidazole-5-carboxylic acid ethyl. Preparation of the ester (compound 7)

1.4 g (3 mmol) of the compound prepared in Example 5 (e), 825 mg (6 mmol) of potassium carbonate in 25 mL of abs. A mixture of DME and ethyl acetate (0.35 mmol, 3.05 mmol) was refluxed for 3 hours, evaporated and the pH adjusted to about 5 with 10% potassium dihydrogen phosphate solution. and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 1.45 g of the title compound having an Rf of 0.3 (silica gel, EA).

Mass Spectrum (FAB): 532 (M + H).

Example 8 1 - {[2 '- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-ethyl-4- (methylthio) imidazole-5 Preparation of ethyl carboxylic acid (Compound 8)

The compound prepared in Example 7 (300 mg, 0.56 mmol) was treated with abs. in toluene, refluxed with n-propylamine (1.5 mL) for 3 hours, evaporated and chromatographed on silica gel. Elution with ethyl acetate gave 130 mg of the title compound, m.p. 202-203 ° C, Rf 0.24 (silica gel, EA).

Mass Spectrum (FAB): 545 (M + H).

······························································•

Example 9 1 - {[2 '- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2-ethyl-4- (methylthio) imidazole-5 Preparation of a carboxylic acid (compound of formula 9)

The title compound was prepared from the compound prepared in Example 8 following the procedure described in Example 2; Starting from 100 mg (0.18 mmol) of starting material, 70 mg of the title compound are obtained, m.p. 135-140 DEG C., Rf = 0.1 (on silica gel, EA).

Mass Spectrum (FAB): 517 (M + M).

Example 10 1 - {[2 '- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylsulfonyl) - Preparation of Imidazole-5-carboxylic acid ethyl ester (Compound 10)

95.0 mg (0.17 mmol) of the compound of Example 1 (the title compound of Example 1) and 10 ml of abs. To the mixture of DKM at -78 ° C was added 59 mg (0.17 mmol) of 50% m-chloroperbenzoic acid, stirred for 20 minutes, then 10 ml of 10% sodium bisulfite solution was added and the solution was allowed to reach room temperature. warm, and after separation of the phases, extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to give 110 mg of the title compound, m.p. 65-68 ° C, Rf = 0.1 (silica gel, EA).

Mass Spectrum (FAB): 575 (M + M).

· * * · * · * * * »· ·» »!!

Example 11 1 - {[2 '- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylsulfoxyl) - imidazole-5-carboxylic acid (Compound 11)

The title compound was prepared from the compound prepared in Example 10 following the procedure described in Example 2; The starting compound (100 mg, 0.17 mmol) gave the title compound (82 mg), m.p. 105-108 'C, Rf = 0.1 (on silica gel, EA).

Mass Spectrum (FAB): 547 (M + M).

Example 12 1 - {[2 '- (n-Propylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylsulfonyl) - Preparation of Imidazole-5-carboxylic acid ethyl ester (Compound 12)

350 mg (0.64 mmol) of the compound prepared in Example 3 are treated with 443 mg (1.28 mmol) of 50% m-chloroperbenzoic acid in 20 ml of abs. Reflux for 1 hour in DKM. Work up as in Example 10 to obtain 364 mg of the title compound as a colorless foam, Rf 0.74 (silica gel, DKM / MCOH (9: 1)).

Mass Spectrum (FAB): 578 (M + H).

Example 13 1 - {[2 '- (Ethoxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylsulfonyl) imidazole-5- preparation of the carboxylic acid (13)

From the compound prepared in Example 12 (120 mg, 0.2 mmol), 84 mg of the title compound was obtained in the same manner as in Example 2 (4). ♦ · · · 4 ··

4444 4 · 4 ···· ···, m.p. 156-159 ° C, Rf 0.5 (silica gel, DKM / MCOH 9: 1).

Example 14 1 - {[2 '- (Ethylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylsulfonyl) imidazole Preparation of ethyl 5-carboxylic acid (Compound 14)

The compound prepared in Example 1 (j) (200 mg, 0.42 mmol) was treated with ethyl isocyanate (34 μΐ, 0.42 mmol).

Example 1 (k) gave 170 mg of the title compound, m.p. 161-162 ° C, Rf 0.43 (on silica gel, EA).

Mass Spectrum (FAB): 545 (M + H).

Example 15 1 - {[2- (Ethylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylsulfonyl) imidazole Preparation of 5-carboxylic acid (compound 15) from mg (0.11 mmol) of the compound prepared in Example 14

According to the procedure of Example 2, 56 mg of the title compound is obtained, m.p. 131 DEG C., Rf = 0.2 (silica gel, DKM / methanol 10: 1).

Mass Spectrum (FAB): 517 (M + H).

Example 16

1 - {[2 '- (allylamino-butoxycarbonylamino) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5-carboxylic acid Preparation of ethyl ester (16)

200 mg (0.42 mmol) of the compound prepared in Example 1 (j) was reacted with 38 μΐ (0.42 mmol) of allyl isocyanate according to the procedure of Example 1 (k) to give 150 mg of the title compound. · ················································································································································································································ · C, Rf 0.43 (silica gel, EA).

Mass Spectrum (FAB): 557 (M + H).

Example 17 1 - {[2 '- (Allylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole. Preparation of 5-carboxylic acid (compound 17) from mg (0.1 mmol) of the compound prepared in Example 16

Example 2 gave 54 mg of the title compound, m.p. 148 DEG C., Rf 0.3 (silica gel, DKM / MCOH 10: 1).

Mass Spectrum (FAB): 529 (M + H).

Example 18 1 - {[2 '- (Methoxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5- Preparation of a carboxylic acid (Compound 18)

500 mg (1.06 mmol) of the compound prepared in Example 1 (j), 293 mg (2.12 mmol) of potassium carbonate, 106 ml (1.06 mmol) of dimethyldicarbonate, 53 mg of DMAP and 20 ml of diethylene glycol dimethyl ether was refluxed for 2 hours, evaporated on a rotary evaporator and the residue was mixed with ethyl acetate / potassium dihydrogen phosphate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 2: 1 ethyl acetate: heptane, to give 225 mg of the title compound, m.p. 146 'C, Rf 0.37 (silica gel, EA).

··· «1 • '9 ·

- · · _ ♦ 9 · · · * ···· · »· A» ·· ···

- 32 Mass Spectrum (FAB): 532 (M + H).

Example 19 l - {[2 ¹ - (methoxy-amino-sulfonyl) -biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5- Preparation of a carboxylic acid (compound of formula 19)

150 mg (0.263 mmol) of the compound of Example 18 are obtained in a manner similar to that described in Example 2, giving 110 mg of the title compound, m.p. 131 ° C, Rf 0.15 (silica gel, DKM / MCOH 10: 1).

Mass Spectrum (FAB): 504 (M + H).

Example 20 1 - {[2 '- (Cyclopropylmethylaminocarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) - Preparation of Imidazole-5-carboxylic acid ethyl ester (Compound 20)

500 mg (1.06 mmol) of the compound obtained in Example 1 (j), 408 mg (1.06 mmol) of dihydroxybenzotriazolyl carbonate (70%), 85 ml (1.06 mmol) of pyridine and 20 ml of abs. . After stirring for 2 hours at room temperature, DKM was treated with cyclopropylmethylamine hydrochloride (114 mg, 1.06 mmol) and pyridine (170 mL, 2.12 mmol) and stirred for a further 2 hours. At this time, the solution was evaporated on a rotary evaporator, the residue was taken up in ethyl acetate, the ethyl acetate layer was washed with sodium bicarbonate solution and then with sodium hydrogen sulfate solution, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate: heptane 1: 3, to give the title compound (72 mg).

33 reds, m.p. 125 'C, Rf 0.47 (on silica gel, EA).

Mass Spectrum (FAB): 571 (M + H).

Example 21

1 - {[2 '- (Cyclopropyl-methyl-amino-carbonyl-amino) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5 -Carboxylic acid (compound 21) mg (0.08 mmol) of the compound prepared in Example 20

Hydrolysis as described in Example 2 gave 34 mg of the title compound, m.p. 138 ° C, Rf = 0.1 (silica gel, DKM / MCOH 9: 1).

Mass Spectrum (FAB): 543 (M + H).

Example 22

1 - {[2 '- (propyl-butyloxycarbonyl-amino) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5-carboxylic acid Preparation of ethyl ester (compound 22)

The compound prepared in Example 1 (j) (200 mg, 0.42 mmol) was reacted with propyl chloroformate (70 mL, 0.63 mmol) in the same manner as in Example 3 and chromatographed on silica gel. Elution with 2: 1 ethyl acetate / heptane gave 200 mg of the title compound, m.p. 144 'C, Rf 0.54 (silica gel, EA).

Mass Spectrum (FAB): 560 (M + H).

Example 23

1 - {[2 '- (propyl-butyloxycarbonyl-amino) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5-carboxylic acid (Compound 23)

The title compound was prepared according to Example 22.

- obtained from 34 compounds according to the procedure of Example 2,

mp 124 ° C, Rf 0.1 (silica gel, DKM / MCOH 10: 1).

Mass Spectrum (FAB): 532 (M + H).

Example 24

1 - {[2 '- (Benzyloxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole-5-carboxylic acid Preparation of ethyl ester (Compound 24)

The compound prepared in Example 1 (j) (200 mg, 0.42 mmol) was treated with benzyl chloroformate (89 μΐ, 0.633 mmol) in a similar manner to Example 3 and chromatographed on silica gel. Elution with 2: 1 ethyl acetate / heptane gave 250 mg of the title compound, m.p. 158 ° C, Rf 0.55 (silica gel, EA).

Mass Spectrum (FAB): 608 (M + H).

Example 25 1 - {[2 '- (Benzyloxycarbonylaminosulfonyl) biphenyl-4-yl] methyl} -2- (n-propyl) -4- (methylthio) imidazole. Preparation of 5-carboxylic acid (25)

The title compound was prepared from the compound of Example 24 according to the procedure of Example 2, mp 115 ° C, Rf 0.1 (silica gel, DKM / MCOH 15: 1).

Mass Spectrum (FAB): 580 (M + H).

Claims (7)

Claims Compounds of formula (I) and their physiologically acceptable salts, characterized in that R 1 is C 1-3 alkyl, R ² is C 1-6 alkyl, C 3-7 cycloalkyl, phenyl or benzyl; R ³ is hydrogen, -CH ₂ OR ⁵ , -CO-R ^6, or -OR ⁷ ; ^R4 -SO2NR ⁷ R ^8, -SO2NR ⁸ -CO-NR ⁷ R ^9, -SO 2 ^-NH-COO-R7, -SO2-NH-SO ₂ NR ⁷ R ^9, -SO 2 -NH-CO-R ⁷ , -SO 2 -NH-SO ₂ -R ⁷ or -SO ₂ N = CH-N (CH 3) ₂ ; R ⁵ is hydrogen or C 1-6 alkyl; R ⁶ is hydrogen or -OR ⁷ ; R ⁷ and R ⁹ are the same or different and are hydrogen; C 1-6 alkyl; C3-C8 cycloalkyl; (C3-C6) cycloalkyl (C1-C3) alkyl; C 6 -C 12 aryl, preferably phenyl; (C 6 -C 10 aryl) (C 1 -C 4) alkyl, (C 1 -C 9) heteroaryl; which may be partially or fully hydrogenated; (C1-C9-heteroaryl) -C1-C3-alkyl, the heteroaryl of which may be partially or fully hydrogenated; mono- or disubstituted C 6 -C 12 aryl, preferably phenyl, C 6 -C 10 aryl, mono- or disubstituted with the same or different halogen, hydroxy, (C 1 -C 4) alkyl, methoxy, nitro or cyano groups (I) (C 4 -C 4 alkyl), (C 1 -C 9) heteroaryl which is partially or fully hydrogenated, or (C 1 -C 9) heteroaryl (C 1 -C 3) alkyl, the heteroaryl of which may be partially or fully hydrogenated; or (C 2 -C 6) alkenyl or (C 3 -C 6) alkenoyl; C3-C8 cycloalkenyl; (C3-C8) cycloalkenyl (C1-C3) alkyl; (C 6 -C 10 aryl) (C 3 -C 6) alkenyl; (C 1 -C 9 heteroaryl) (C 3 -C 6 alkenyl); or C 3-6 alkynyl; R ^{8 is} hydrogen; and n is 0, 1 or 2. Compounds according to claim 1 and their physiologically acceptable salts, wherein in the formula (I) R ^{1 is} ethyl or n-propyl. Compounds according to Claim 1 and their physiologically acceptable salts, characterized in that in formula (I) R ^{1 is} n-propyl. 4. Compounds according to any one of claims 1 to 3 and their physiologically acceptable salts, characterized in that R ² is C 1-6 alkyl; R ³ is -COR ⁶ ; n is 0; R ⁴ is -SO 2 -NH-CO-OR ⁷ , -SO ₂ NHCO-NHR ⁷ or -SO ₂ -NH-CO-R ⁷ ; • * · * • ·· ♦ · «« - 37 R ^{6 is} hydrogen or -OR ⁷ ; and R ⁷ is hydrogen or C 1-6 alkyl. 5. A pharmaceutical composition having an angiotensin-II receptor antagonist activity for the treatment of hypertension, heart failure, atherosclerosis and cerebral anemia, characterized in that the active substances according to any one of claims 1-4. A compound of formula (I), or a physiologically acceptable salt thereof, as claimed in any one of claims 1 to 6 in admixture with customary diluents, carriers and / or excipients. A process for the preparation of a compound of formula (I) and physiologically acceptable salts thereof, wherein R ¹ , R ² , R ³ , R ⁴ and n are as defined in claim 1, characterized in that a compound of formula (I) Compound II, where R ¹ , R ² , R ³ and n are as defined above, is alkylated with a compound of formula III, wherein R ⁴ is as defined above and U is a leaving group, followed by the cleavage of any temporary protecting groups, optionally converting a sulfonamide of formula (I) thus obtained into a urethane of formula (I), optionally converting a sulfonamide of formula (I) thus obtained into a sulfonylurea of formula (I) and optionally converting a sulfonamide of formula (I) ) is converted to a physiologically acceptable salt. 7. Angiotensin II Receptor Antagonist In Hypertension, Heart Failure, Atherosclerosis and Brain • · · · · · 38 for the preparation of a pharmaceutical composition for the treatment of anemia, wherein the active ingredient is a compound of the formula I as claimed in claim 6, wherein R ¹ , R ² , R ³ , R ⁴ and n are as defined in claim 6, or a physiologically acceptable salt thereof, in admixture with diluents, carriers and / or excipients which are conventional in the pharmaceutical formulation to form a pharmaceutical composition.